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REVIEW ARTICLE Table of Contents   
Year : 2001  |  Volume : 7  |  Issue : 3  |  Page : 85-94
Hepatopulmonary syndrome

Department of Gastroenterology, King Fahad Central Hospital, Abu Arish, Saudi Arabia

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Date of Submission11-Mar-2001
Date of Acceptance01-Jul-2001

How to cite this article:
Gadour ME, Ayoola A, Yousuf AZ, El Sammani EE. Hepatopulmonary syndrome. Saudi J Gastroenterol 2001;7:85-94

How to cite this URL:
Gadour ME, Ayoola A, Yousuf AZ, El Sammani EE. Hepatopulmonary syndrome. Saudi J Gastroenterol [serial online] 2001 [cited 2022 Aug 16];7:85-94. Available from:

   Introduction Top

The interaction between the lung and the liver had been well recognized since the nineteenth century [1] . The liver plays an important role in regulating pulmonary vascular tone. Therefore, patients with hepatic dysfunction and portal hypertension have a wide range of pulmonary vascular disorders that include intrapulmonary vascular dilatations [IPVD], gas exchange impairment and pulmonary hypertension. In the latter the pulmonary vascular resistance is elevated, leading occasionally to haemodynamic failure.

In 1977, Kennedy and Knudson suggested the term "hepatopulmonary syndrome [HPS]" for the functional pulmonary insufficiency associated with liver disease [2] . Thus, the syndrome is defined as the triad of liver dysfunction, an increased alveolar­arterial oxygen gradient to> 15 mmHg while breathing room air, and reversible intrapulmonary vascular dilatations in the absence of intrinsic cardiopulmonary disease. However in 20-30% of patients with HPS, other cardiopulmonary abnormalities may coexist, leading to a lower oxygen tension [P0 2 ] when breathing room air or 100% oxygen [0 2 ] [3],[4] . Although impaired arterial oxygenation [P0 2 < 60 mm Hg] is the physiological hallmark of the syndrome, patients with liver cirrhosis and HPS commonly have alveolar hyperventilation with hypocapnia. Therefore, alveolar-arterial oxygen gradient is considered to be a more accurate albeit, less practicable measure of cardiorespiratory dysfunction than p0 2 or carbon dioxide tension [pCO 2 ] in patients suspected to have HPS. IPVD, the structural hallmark of the syndrome seems to contribute significantly to the low pulmonary vascular resistance and hence the reduced pulmonary arterial pressure characteristically observed in the syndrome.

   Clinical Features Top

In the majority of patients, the symptoms and signs of the liver disease overshadow pulmonary features comprising dyspnea, platypnea, and ortbodeoxia. Of these dyspnea is the commonest occurring as the presenting symptom in 18% of the patients reported by some authors [5] . Platypnea and orthodeoxia, both induced by the upright position and relieved by recumbency are present in 5-88% of patients with liver cirrhosis [5],[6],[7] . However, both are not pathognomonic of the HPS as they may be associated with other diseases such as postpneumonectomy state, recurrent pulmonary embolism, intracardiac shunting, and aortic aneurysm combined with aneurysm of the atrial septum [8],[9]

Patients with spider naevi who develop the HPS, are noted to have more systemic and pulmonary vasodilatation, more profound gas exchange abnormalities, and less hypoxic pulmonary vasoconstriction [6],[10] This observation has led to the suggestion that spider naevi constitute a cutaneous marker of IPVD [11] . Also, some authors suggested that cyanosis may be the only reliable clinical indicator [12] . The presence of significant peripheral pulmonary vasodilatation may be helpful in the diagnosis of HPS [13] In cirrhotic patients, especially alcoholics, with normal oxygen tension, the vasodilatation and gas-exchange abnormalities may be sub-clinical [14],[15]

Occasionally these abnormalities have been reported to precede the clinical appearance of the liver disease. In fact, hypoxemia may worsen over time without any clinical or biochemical deterioration of liver function [5] . Rarely, such abnormal gas exchanges may become evident only after liver transplantation.

   Mechanisms of Hypoxemia Top

The increased cardiac output and IPVD are thought to be important factors in the development of the HPS. Patients with liver cirrhosis and the HIPS have increased cardiac output of about 7L/min. About 20% to 70% of this is conducted by the IPVD resulting in a short transit time for the blood in the lungs. When breathing a normal room air, the 0 2 drive is enough to oxygenate the red blood cells at the center of the normal pulmonary vessels [Figure - 1]

In patients with the HPS who have dilated capillaries oxygen molecules from adjacent alveoli cannot diffuse to oxygenate hemoglobin in erythrocytes at the center stream of venous blood [Figure - 2]. This inadequate oxygenation is enhanced by the short transit time of the hyperdynamic circulation, which does not provide the red blood cells enough time in contact with the alveoli to acquire good amount of oxygen. When such a patient is in the upright position a disproportionately larger amount of the blood in the pulmonary circulation preferentially flows to the dilated vessels in the hypoventilated lung bases. This further enhances diffusion­perfusion impairment leading to platypnea and orthodeoxia. Unlike what occurs in true anatomical shunts, supplemental oxygen provides enough driving pressure to partially overcome the relative diffusion defect in HPS [Figure - 3].

Exercising patients with cirrhosis or HPS while breathing room air or 100% oxygen had caused further impairment of oxygenation, development of wider alveolo-arterial oxygen gradient and larger shunt fraction [16] . This may be explained at least in part, by the shortened transit time. The effect of exercise is more pronounced in patients with the HPS who already demonstrate a severe reduction in aerobic capacity beyond the levels seen in cirrhotics without the syndrome [16]

Normal pulmonary vascular tone is essential for maintaining adequate ventilation / perfusion equation that maintain normal oxygenation. A high or low tone disturbs the equation and leads to hypoxemia. Although the IPVD causing diffusion­-perfusion impairment is considered to be the most important factor underlying impaired gas exchange and resulting in severe hypoxemia characteristic of the HPS, it is not enough alone to diagnose HPS as it may not be associated with severe hypoxemia.

   Pathogenesis Top

The pathogenesis of HPS is poorly understood and the exact mediator of the IPVD characteristic of the HPS remains obscure. However several mechanisms with different mediators have been postulated [Table - 1]. The most popular hypothesis is that of increased circulating pulmonary vasodilators, where the damaged liver plays a crucial role either by over production or failure to clear a circulating pulmonary vasodilator. The mediator of this vasodilatation is not well established. There is a wide range of possible substances in this category starting from an unknown mediator going through the vasodilator prostaglandins, vasoactive intestinal peptide, calcitonin, glucagon, substance P, atrial natriuretic factor, and platelet-activating factor [11] to nitric oxide [NO], which has gained recently more support as the likely mediator.

NO is a labile, highly reactive, diffusible gas that is produced by many tissues, especially the endothelia of the vascular bed and the neurones. It is a potent vasodilator that exerts a range of physiological and pathophysiological effects [17] . There is an increased level of endothelin 1 in patients with portal hypertension possibly due to shear stress in endothelial cells caused by hyperkinetic circulation and also during hepatic injury [18] . This endothelin 1, by modulating synthase significantly contributes to the increased levels of NO found in patients with liver cirrhosis [19],[20] . By reducing the pulmonary vascular tone NO significantly vasodilates the pulmonary vascular bed leading to deterioration of ventilation / perfusion equation and hence attenuates gas exchange resulting in hypoxemia. There is significant correlation between exhaled NO and alveolo-arterial 0 2 gradient. The correlation between the decrease in exhaled NO concentration after liver transplantation and the improvement in oxygenation reinforces the hypothesis that NO is an important mediator of impaired oxygenation and circulatory abnormalities in patients with cirrhosis [21] .The measurement of NO in the exhaled air may represent a possible measure of gas exchange abnormalities in liver disease.

Common bile duct ligation [CBDL] in animals results in progressive hepatic injury and portal hypertension accompanied by gas-exchange abnormalities and intrapulmonary vasodilatation similar to that of the HPS [22] . This may be due to the enhanced hepatic production and increased plasma levels of endothelin-1 in this condition, which may contribute to the pathogenesis of HPS [23] .

The second hypothesis is that of inhibition by the damaged liver of a circulating unknown vasoconstrictive substance. It has been found that impaired vascular responsiveness to the potent vasoconstrictor angiotensin II is also common in rats with liver cirrhosis and this may be mediated by the high level of NO as the response can be reverted to normal by inhibiting NO or by infusing more angiotensin 11 [24] . Those proposing that circulating vasoconstrictors are inhibited or metabolized in the HPS have implicated several vasoconstrictors, including tyrosine, serotonin, and endothelin 1, but little proof of their role in the HPS is available [25],[26]

Hypoxemic pulmonary vasoconstriction has a fundamental role in maintaining normoxemia by diverting blood away from hypoventilated areas in the lungs; impairment of this pulmonary vasoconstriction in response to hypoxemia by an unknown mechanism - is hypothesized to be the third element precipitating the HPS [27] .

Although unproven, exclusion of hepatic venous blood from the lungs has been proposed as a possible cause of HPS through an unknown mechanism. This is based on the observation that pulmonary arterovenous malformations occur in 25% of patients who had Glenn shunt and that this can be reverted by resuming the hepatic blood flow to the right atrium [28]

   Diagnosis Top

Routine investigations: In the assessment of patients suspected to have HPS, intrinsic cardiorespiratory diseases should be excluded and by using conventional methods, the presence of hepatic dysfunction needs to be confirmed. Routine investigations are not helpful in the diagnosis of HPS. Blood counts and biochemistry may be normal or may be attributable to the primary liver disease itself.

Chest radiographs may appear normal or show the abnormalities that generally occur in patients with cirrhosis. The latter include evidence of decreased lung volumes as was observed in 57%, pleural effusions [19.3%], increased interstitial markings [in 13.8%], and increased pulmonary vascular markings [3.7%] [29] . The characteristic appearance of increased bibasilar nodular or reticulonodular opacities, representing dilated interstitial and pulmonary vascular bed in the clinical setting of liver dysfunction and hypoxemia highly suggests the presence of the HPS These radiographic findings alone are not enough to make the diagnosis of HPS. Under these circumstances high resolution CT may be helpful in excluding pulmonary fibrosis and other interstitial lung diseases [30] . Interstitial markings in patients with HPS may be minimal and characterized by a finely diffuse, spidery infiltrates at the pre­capillary level close to gas-exchange units of the lung [Type 1]. This maybe associated with severe hypoxemia and orthodeoxia that has a good response to 100% inspired oxygen.

This minimal type is liable to change to the advanced pattern [Type 2] that is characterized by discrete, localized arteriovenous communications distant from gas-exchange units, resulting in a diffuse spongy or blotchy angiographic appearance. This type is less responsive to 100% oxygen [5] . Although this classification, may have some therapeutic and prognostic implications, the description was based on a few patients with the HPS and therefore its application must await further supplementary studies.

Lung perfusion scans: By offering a possible means to. semiquantitate the severity of IPVD and assisting in distinguishing vascular from non-vascular reasons for hypoxemia, a lung perfusion scan can be a reliable and efficient method for the determination of patients' progress during follow up [31]

Assessment of gas exchange: Detecting hypoxemia with increased alveolar-arterial oxygen gradient while the patient is breathing room air in an upright position that improves on recumbency or with 100% 0 2 supplement is essential for the diagnosis of the syndrome. Failure to improve p0 2 on 100% 0 2 , inspiration usually indicate the presence of true arteriovenous shunts.

Special investigations: Diagnosis of IPVD needs special investigations, depending mainly on imaging techniques, which include: Contrast-enhanced echocardiography, radiolabeled macro-aggregated albumin scanning, and pulmonary arteriography.

Contrast-Enhanced Echocardiography: Contrast­enhanced transthoracic echocardiography [CTTE] is the most valuable screening test in detecting IPVD in the early stages of hepatic insufficiency [21] Contrast-enhanced transoesophageal echocardiography [CTEE] is more sensitive and has a better correlation with gas-exchange abnormalities than CTTE. Despite its semi-invasiveness, CTEE is recommended in the diagnosis and grading of pulmonary vasodilatation all patients in whom HPS is suspected especially when CTTE is normal [32]

Indocyanine green dye or agitated saline that provides a stream of microbubbles 60 to 90 microns in diameter is used usually. Both opacify only the right heart chambers [33],[34] They are trapped and filtered by the finer [8 microns] pulmonary capillary bed and therefore do not appear in the left side of the heart in normal lungs [35] . However, in the presence of an LPVD or intracardiac right-to-left shunt, these items opacify the left heart chambers either by traversing the lung in the former condition or going directly through the shunt in the latter [25],[34],[36] The precise timing of opacification of the left heart chambers in relation to the initial appearance of the dye or bubbles in the right heart is critical for the differentiation between intracardiac and intrapulmonary shunt. When there is an intracardiac right-to-left shunt, a shorter time is required for opacification of the left heart [11],[37]

Additionally, CTEE is very helpful in choosing the modality of treatment by detecting localized major 1PVDs, which are more amenable to surgical or embolic intervention compared to the diffuse, bilateral arteriovenous communications, which require other modalities of treatment. However, contrast-enhanced echocardiography cannot differentiate among precapillary, capillary, or pleural dilatations and direct arteriovenous anastomoses [38]

Technetium99m Macro-Aggregated Albumin scan: Similar to indocynate dye and agitated saline technetium 99m-labeled macro aggregated albumin [99TcMAA] exceeding 20-25 microns in diameter are usually trapped and filtered by the normal pulmonary capillary bed [diameter 8 microns]. In normal patients, only 3% to 6% of albumin macroaggregates traverse through the pulmonary vascular bed to the systemic circulation [6],[39] . The appearance of radioactivity over the kidneys or brain indicates passage of a significant amount of these particles through the lungs and suggests an intrapulmonary vasodilatation or an intracardiac shunt. The magnitude of this shunt is, estimated by calculating the ratio of systemic to total body activity of the radionuclide [39]

Pulmonary arteriography: Because of its invasiveness, pulmonary angiography is often reserved for patients with severe hypoxemia and a poor response to 100% oxygen [0 2 ]. It is however useful in the exclusion of arterio-venus fistula, the provision of hemodynamic measurements and the visualization of IPVD. Secondly, it helps in determining large localized dilated vessels suitable for spring-coil embolization as a therapeutic option.

By using micro-opaque gelatin as a contrast, spider nevi on the pleura, dilatation of the fine peripheral branches of the pulmonary artery at both the precapillary and capillary levels can be demonstrated [40] . Nevertheless, it is not uncommon for angiogram to be reported as normal in patients with the HPS. Also, the characteristics of the vascular patterns seen in HPS may be indistinguishable from those obtained months after the creation of cavopulmonary surgical connection performed to improve pulmonary blood flow [41]

   Treatment Top

To date there is no effective specific medical treatment for the HPS. Recovery of hepatic normal function either spontaneously or through treating the underling liver disease - if possible - results in resolution of the syndrome. Some patients may recover spontaneously as a result of the development of pulmonary hypertension, which reverts the IPVD [42] .

Simple measures and manoeuvre may temporary help these patients and ameliorate their symptoms. Inhalation of 100% O 2 can be very helpful in relieving the symptoms and constitute a reasonable method to tide the patients over the pre-transplant period or in the early postoperative phase Positioning in recumbency or Trendelenburg's position with continuous lateral rotation may be rewarding in those patients waiting for liver transplantation by positively improving the PO 2 either on room air or while on 100 percent oxygen [43]

Many therapeutic modalities have been tried to reverse HPS with unsatisfactory results. These included an attempt to remove this unknown mediator of the HPS by plasma exchange [5] ; drugs to directly increase pulmonary vascular tone or as antidotes to the assumed mediators.

Trials with garlic (allium sativurn) [44] indomethacin [45] , almitrine bismesylate [46] gave controversial results, which in general are not satisfactory. Octreotide, being reported initially to improve oxygenation, was shown by recent studies to lack efficacy whether given by subcutaneous or intravenous routes [5],[47]

In a patient methylene blue, an oxidizing agent that blocks the stimulation of soluble guanylate cyclase by NO, was found to decrease pulmonary shunting significantly [48] . Therefore the reduction of NO level by inhibiting its production or blocking its effect by giving its antidotes remains a challenge to investigators.

Transjugular intrahepatic portosystemic shunt [TIPSS] is assumed to represent a reasonable temporal therapy for those waiting for liver transplantation or even durable treatment option for some patients especially those with non-cirrhotic portal hypertension [49] . Spring-coil embolization therapy although not a definitive treatment for HPS may provide a good palliation by improving oxygenation and exercise tolerance when used in selected patients with large localized IPVD.

Based on the complete or partial reversibility of the physiological, biochemical clinical and hemodynamic changes following the procedure, liver transplantation [LT] has emerged as a possible curative treatment for the HPS. However, the outcome is unpredictable.

Although severe disabling hypoxemia is now considered as an indication for LT, the effect of the severity of pre transplantation, intra- and post­operative hypoxemia remains a great concern to treating doctors. A preoperative P0 2 of less than 60 mm Hg on room air constitutes a high risk for surgery-related mortality [50] . Following LT, the 1­year survival ranging from 16 to 30% seems to be greatest in patients with a pretransplant p0 2 <50nmiHg and 99TcMAA lung perfusion scan with brain uptake >30%[normal 5% [51],[52] Correction of hypoxemia may be delayed up to 15 months postoperatively and transient deterioration may occur during this period [53] . The initial response of hypoxemia to 100% 02 breathing appears to be an important prognostic factor in pre-operative death rate. Unfortunately, selecting patients and predicting outcome remains a challenge requiring further studies.

   Prognosis Top

HPS has no specific relation with the severity of hepatic dysfunction, the Child classification the clinical picture or the etiology of the liver disease [3],[12] Correlation between the severity of esophageal varices and the syndrome has been suggested [54] . The major morbidity and mortality in patients with the HPS are those of the liver disease and its complication. Rarely pulmonary morbidity may predominate. It is interesting to note that HPS-like physiology was reported in association with metastatic carcinoid in a patient with intact liver function and in patients with non cirrhotic portal hypertension, inferior vena cava [suprahepatic] obstruction, schistosomal and sarcoid liver disease as well as after bone marrow transplantation [1],[55],[56],[57] .

   Summary Top

The interaction between the lung and the liver had been well recognized since the 19 th century, leading to a wide spectrum of diseases. One of these is the hepatopulmonary syndrome which is defined as the triad of liver dysfunction, an increased alveolar­arterial oxygen gradient to> 15 mmHg while breathing room air, and reversible intrapulmonary vascular dilatations in the absence of intrinsic cardiopulmonary disease. Hepatopulmonary syndrome has no specific relation with the severity of hepatic dysfunction, the clinical picture or the etiology of the liver disease. However, in the majority of patients, the symptoms and signs of the liver disease overshadow pulmonary features. The pathogenesis and the exact mediator of intrapulmonary vascular dilatations characteristic of the syndrome remain obscure. The most popular hypothesis is that of increased circulating pulmonary vasodilators, where the damaged liver plays a crucial role either by over production or failure to clear a circulating pulmonary vasodilator. Beside routine tests, special investigations are required to diagnose intrapulmonary vascular dilatations depending mainly on imaging techniques, which include: Contrast-enhanced echocardiography, radio-labeled macro-aggregated albumin scanning, and pulmonary arteriography.

To date there is no effective specific medical treatment for the hepatopulmonary syndrome. Recovery of hepatic normal function is either spontaneously or through treating the underling liver disease -if possible- results in resolution of the syndrome.

   References Top

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Correspondence Address:
Ayobanji Ayoola
Dept. of Gastroenterology, King Fahad Central Hospital, P.O. Box 235, Abu Arish
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

PMID: 19861775

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